Cladribine regimen for treating multiple sclerosis

ABSTRACT

The present invention is related to the use of Cladribine for the preparation of a pharmaceutical formulation for the treatment of multiple sclerosis, especially relapsing-remitting multiple sclerosis or early secondary progressive multiple sclerosis, wherein the preparation is to be orally administered and wherein re-treatments are possible.

CROSS-REFERENCE TO RELATED APPLICATION

This application is the U.S. national stage application of InternationalPatent Application No. PCT/EP2005/056954, filed Dec. 20, 2005, whichclaims the benefit of U.S. Provisional Patent Application No.60/638,669, filed Dec. 22, 2004, the disclosures of which are herebyincorporated by reference in their entireties, including all figures,tables and amino acid or nucleic acid sequences.

FIELD OF THE INVENTION

The present invention relates to the use of multiple doses of Cladribinefor the treatment of multiple sclerosis, especially relapsing-remittingmultiple sclerosis or early secondary progressive multiple sclerosis.

BACKGROUND OF THE INVENTION

Multiple sclerosis (MS) is the most known chronic inflammatorydemyelinating disease of the central nervous system in humans. The onsetof the disease typically occurs during ages 20 to 40. Women are affectedapproximately twice as often as men.

Over time, MS may result in the accumulation of various neurologicaldisabilities. Clinical is disability in MS is presumed to be a result ofrepeated inflammatory injury with subsequent loss of myelin and axons,leading to tissue atrophy.

MS is manifested in physical symptoms (relapses and disabilityprogression), Central Nervous System (CNS) inflammation, brain atrophyand cognitive impairment. Presenting symptoms include focal sensorydeficits, focal weakness, visual problems, imbalance and fatigue. Sexualimpairment and sphincter dysfunction may occur. Approximately half ofthe patients with MS may experience cognitive impairment or depression.

MS is now considered to be a multi-phasic disease and periods ofclinical quiescence (remissions) occur between exacerbations. Remissionsvary in length and may last several years but are infrequentlypermanent.

Four courses of the disease are individualized: relapsing-remitting(RR), secondary progressive (SP), primary progressive (PP) andprogressive relapsing (PR) multiple sclerosis.

More than 80% of patients with MS will initially display a RR coursewith clinical exacerbation of neurological symptoms, followed by arecovery that may or may not be complete (Lublin and Reingold,Neurology, 1996, 46:907-911).

During RRMS, accumulation of disability results from incomplete recoveryfrom relapses. Approximately, half of the patients with RRMS switch to aprogressive course, called SPMS, 10 years after the diseased onset.During the SP phase, worsening of disability results from theaccumulation of residual symptoms after exarcerbation but also frominsidious progression between exacerbations (Lublin and Reingold above).10% of MS patients have PPMS which is characterized by insidiousprogression of the symptoms from the disease onset. Less than 5% ofpatients have PRMS and are often considered to have the same prognosisas PPMS. It is suggested that distinct pathogenic mechanisms may beinvolved in different patient sub-groups and have wide-rangingimplications for disease classification (Lassmann et al., 2001, TrendsMol. Med., 7, 115-121; Lucchinetti et al., Curr. Opin. Neurol., 2001,14, 259-269).

MS onset is defined by the occurrence of the first neurological symptomsof CNS dysfunction. Advances in cerebrospinal fluid (CSF) analysis andmagnetic resonance imaging (MRI) have simplified the diagnostic processand facilitated early diagnostic (Noseworthy et al., The New EnglandJournal of Medicine, 2000, 343, 13, 938-952). The International Panel onthe Diagnosis of MS issued revised criteria facilitating the diagnosisof MS and including MRI together with clinical and para-clinicaldiagnostic methods (Mc Donald et al., 2001, Ann. Neurol., 50:121-127).

Current medications for MS which are disease modifying treatments, i.e.modifying the course of MS, modulate or suppress the immune system.There are four FDA approved immunomodulating agents for RRMS: three betainterferons (Betaseron®, Berlex; Avonex®, Biogen; Rebif®, Serono) andGlatimarer Acetate (Copaxone®, Amgen). There is also one FDA approvedimmunosuppressing drug for worsening MS, Mitoxantrone (Novantrone®,Amgen). Several other immunosuppressive agents are used, although notFDA approved.

Among them, Cladribine, a chlorinated purine analogue2-chloro-2′deoxyadenosine analogue (2-CdA), has been suggested to beuseful in the treatment of MS (EP 626853B1 and U.S. Pat. No. 5,506,214).

Several clinical studies with Cladribine in patients with multiplesclerosis have investigated the use of i.v. and s.c. Cladribine in MS.

Two double-blind, placebo controlled Phase II studies were conductedrespectively in the treatment of Chronic Progressive MS (Selby et al.,1998, Can. J. Neurol. Sci., 25:295-299) and Relapsing-Remitting MSrespectively (Romine et al., 1999, Proceedings of the Association ofAmerican Physicians, 111, 1, 35-44).

In the first trial, the Cladribine dose used was 0.1 mg/kg/day for 7days by continuous i.v. infusion. The treatment for repeated for 4consecutive months.

In the second clinical trial, the Cladribine dose used was 0.07mg/kg/day for 5 days by subcutaneous injection. The treatment wasrepeated for 6 consecutive months.

In addition, placebo controlled Phase III study was conducted inpatients with primary progressive (PP) or secondary progressive (SP)multiple sclerosis (Rice at al., 2000, Neurology, 54, 5, 1145-1155). Inthis study, both patient groups received Cladribine by subcutaneousinjection at a dose of 0.07 mg/kg/day. The treatment was repeated foreither 2 months or 6 months.

The Phase II clinical studies provided evidence for the positive effectsof Cladribine in patients with MS in terms of Kutzke Extended DisabilityStatus Scale (EDSS), Scripps Neurologic rating Scale (SNRS) scores andMagnetic Resonance Imaging (MRI) findings (Beutler et al., 1996, Proc.Nat. Acad. Sci. USA, 93, 1716-1720; Romine et al., 1999 above). Phase IIstudy results, were positive on the significant reduction ofMRI-measured brain lesions (Rice at al., 2000, above).

Some adverse effects (AEs), such as increased incidence of infectionsrelated to compromised immune function or myelosuppression, wereobserved with the highest doses (Selby et al., 1998, above; Beutler etal., 1994, Acta hematol, 91:10-15). Due to the narrow margin of safetybetween the efficacy dose and the dose of occurrence of AEs, to date,all clinical trials for Cladribine in multiple sclerosis have beenconducted using either i.v. or s.c. administration. As a result, Beutleret al. (Beutler et al., 1996, Seminars in Hematology, 33, 1(S1), 45-52)excluded the oral route for the treatment of multiple sclerosis withCladribine.

Grieb et al. reported a small trial in 11 patients withremitting-relapsing multiple sclerosis (Grieb et al., 1995, ArchivumImmunologiae et Therapiae Experimentalis, 43 (5-6), 323-327) whereinCladribine has been orally administered during 6 monthly courses of 5days at a total dose of about 4-5.7 mg/kg (patients of about 52 andabout 75 kilos, respectively) i.e. a total effective dose of 2-2.85mg/kg. For some patients, a single re-treatment of 5 days was performedat a cumulative dose of 0.4-0.66 mg/kg after a cladribine free-period of3 or 6 months. The side effects observed with the regimen above weresaid to be less severe than the ones observed in the study on patientssuffering from chronic progressive multiple sclerosis treated by i.v.infusion of Cladribine (Sipe et al., 1994, Lancet, 344, 9-13) but werestill present. In addition, the therapeutic efficacy of the oral regimenabove versus the i.v. infusion therapy was questioned (Grieb et al.,1995, above) and a group of “non-responders” has been identified(Stelmasiak et al., 1998, Laboratory Investigations, 4(1), 4-8).

Therefore, it would be desirable to have a method for treating multiplesclerosis comprising the oral administration of Cladribine that wouldpermit the same or improved effect on MS lesions while decreasing theoccurrence and/or severity adverse events. In addition, as MS is achronic disease, it would be desirable to decrease the occurrence and/orseverity adverse events in such a way that re-treatments are possible. Asustained benefit of Cladribine treatment between the treatment periodsis also desirable.

SUMMARY OF THE INVENTION

The present invention is directed towards a use of Cladribine for thepreparation of a pharmaceutical formulation for the treatment ofmultiple sclerosis, wherein the preparation is to be the orallyadministered. Particularly, the invention is directed towards a use ofCladribine for the preparation of a medicament for the treatment ofrelapsing-remitting multiple sclerosis or early secondary progressivemultiple sclerosis and wherein re-treatments are possible.

An embodiment of the invention provides an improved dosing regimen forCladribine in the treatment of multiple sclerosis.

An additional embodiment of the invention provides a use of Cladribinefor the preparation of a pharmaceutical formulation for the treatment ofmultiple sclerosis wherein adverse effects are reduced, allowing furtheruse of Cladribine.

In one embodiment, the invention provides a use of Cladribine for thepreparation of a pharmaceutical formulation wherein the formulation isto be orally administered following the sequential steps below:

-   -   (i) An induction period wherein the Cladribine pharmaceutical        formulation is administered and wherein the total dose of        Cladribine reached at the end of the induction period is from        about 1.7 mg/kg to about 3.5 mg/kg;    -   (ii) A Cladribine-free period wherein no Cladribine is        administered;    -   (iii) A maintenance period wherein Cladribine pharmaceutical        formulation is administered and wherein the total dose of        Cladribine reached at the end of the maintenance period is lower        than the total dose of Cladribine reached at the end of the        induction period (i);    -   (iv) A Cladribine-free period wherein no Cladribine is        administered.

In another embodiment, the invention provides a method for the treatmentof multiple sclerosis, comprising the oral administration of Cladribineor of a formulation thereof in a patient in need thereof comprising thefollowing steps:

-   -   (i) An induction treatment wherein the total dose of Cladribine        reached at the end of the induction period is from about 1.7        mg/kg to about 3.5 mg/kg;    -   (ii) A Cladribine-free period wherein no Cladribine is        administered;    -   (iii) A maintenance treatment wherein the total dose of        Cladribine reached at the end of the maintenance period is lower        than the total dose of Cladribine reached at the end of the        induction period (i);    -   (iv) A Cladribine-free period wherein no Cladribine is        administered.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

The “total dose” or “cumulative dose” refers to the total dose ofCladribine administered during the treatment, i.e. the dose reached atthe end of the treatment that is calculated by adding the daily doses.For example, the total dose of Cladribine corresponding to a treatmentof 0.7 mg/kg Cladribine per day during 5 days is 3.5 mg/kg or the totaldose of Cladribine corresponding to a treatment of 0.35 mg/kg Cladribineper day during 5 days is 1.7 mg/kg.

“The total effective dose” or “cumulative effective dose” refers to thebioavailable dose of Cladribine after a given administration period,i.e. the bioavailable dose reached at the end of the treatment that iscalculated by adding the daily doses reduced by the bioavailabilitycoefficient. For example, the total effective dose of Cladribinecorresponding to a treatment of 0.7 mg/kg Cladribine per day during 5days wherein the bioavailability of Cladribine is of about 40% is 1.4mg/kg or the total effective dose of Cladribine corresponding to atreatment of 0.35 mg/kg Cladribine per day during 5 days wherein thebioavailability of Cladribine is of about 40% is 0.7 mg/kg.

Typically, the bioavailability of Cladribine or of a Cladribineformulation used in the context of this invention is from about 30% toabout 90%, preferably from about 40% to about 60%, such as about 50%.

“A week” refers to a period of time of or about 5, about 6 or about 7days.

“A month” refers to a period of time of or about 28, about 29, about 30or about 31 days.

“Treatment” comprises the sequential succession of an “inductiontreatment” and at least a “maintenance treatment”. Typically, atreatment according to the invention comprises an “induction treatment”and about one or about two or about three maintenance treatments.Typically, a treatment according to the invention is of about 2 years(about 24 months) or about 3 years (about 36 months) or about 4 years(about 48 months).

An “Induction Treatment” consists in the sequential succession of (i) aninduction period wherein the Cladribine or the Cladribine pharmaceuticalpreparation of the invention is orally administered and (ii) aCladribine-free period. An induction period lasts up to about 4 monthsor up to about 3 month or up to about 2 months. For example, aninduction period lasts for about 2 to about 4 months. An inductionperiod consists in the oral administration of Cladribine or apharmaceutical preparation thereof during about 1 to about 7 days eachmonth.

A “Cladribine-free period” is a period wherein no Cladribine isadministered to the patient. During a Cladribine-free period, thepatient can be free of any administration or be dosed with aplacebo-pill or another drug except. A Cladribine-free period lasts upto about 10 months or up to 9 months or up to about 8 months. Forexample, a Cladribine-free period lasts from about 8 to about 10 months,typically at least of about 8 months.

A “Maintenance Treatment” consists in the sequential succession of (i) amaintenance period wherein the Cladribine or the Cladribinepharmaceutical preparation of the invention is orally administered at alower dose than the Cladribine dose orally administered during theinduction treatment and (ii) a Cladribine-free period. A maintenanceperiod lasts for up to about 4 months, or up to about 3 months, or up toabout 2 months, preferably up to about 2 months. For example, amaintenance period lasts for about 2 to about 4 months, preferably forabout 2 months. A maintenance period consists in the oral administrationof Cladribine or of a pharmaceutical preparation thereof during about 1to about 7 days each month.

Within the context of this invention, the beneficial effect, includingbut not limited to an attenuation, reduction, decrease or diminishing ofthe pathological development after onset of the disease, may be seenafter one or more a “treatments”, after an “induction treatment”, aftera “maintenance treatment” or during a Cladribine-free period.

“Daily dose” refers to the total dose of Cladribine orally administeredto the patient each day of administration. The daily dose can be reachedthrough a single or several administrations per day, such as for exampleonce a day, twice a day or three times a day.

The dosage administered, as single or multiple doses, to an individualwill vary depending upon a variety of factors, including pharmacokineticproperties, patient conditions and characteristics (sex, age, bodyweight, health, size), extent of symptoms, concurrent treatments,frequency of treatment and the effect desired.

Patients suffering from MS can be defined for example as havingclinically definite or laboratory-definite MS according to Schumacher orPoser criteria (Schumacher et al., 1965, Ann. NY Acad. Sci. 1965;122:552-568; Poser et al., 1983, Ann. Neurol. 13(3): 227-31).

“Relapses” involve neurologic problems that occur over a short period,typically days but sometimes as short as hours or even minutes. Theseattacks most often involve motor, sensory, visual or coordinationproblems early in the disease. Later, bladder, bowel, sexual andcognitive problems may be shown. Sometimes the attack onset occurs overseveral weeks. Typical MS relapse involves a period of worsening, withdevelopment of neurological deficits, then a plateau, in which thepatient is not getting any better but also not getting any worsefollowed by a recovery period. Recovery usually begins within a fewweeks.

“Efficacy” of a treatment according to the invention can be measuredbased on changes in the course of disease in response to a use accordingto the invention. For example, treatment of MS efficacy can be measuredby the frequency of relapses in RRMS and the presence or absence of newlesions in the CNS as detected using methods such as MRI technique(Miller et al., 1996, Neurology, 47(Suppl 4): S217; Evans et al., 1997,Ann. Neurology, 41:125-132).

The observation of the reduction and/or suppression of MRI T₁gadolinium-enhanced lesions (thought to represent areas of activeinflammation) gives a primary efficacy variable.

Secondary efficacy variables include MRI T₁ enhanced brain lesionvolume, MRI T₁ enhanced lesion number, MRI T₂ lesion volume (thought torepresent total disease burden, i.e. demyelination, gliosis,inflammation and axon loss), MRI T₁ enhanced hypointense lesion volume(thought to represent primarily demyelination and axon loss),time-to-progression of MS, frequency and severity of exacerbations andtime-to-exacerbation, Expanded Disability Status Scale score and ScrippsNeurologic Rating Scale (SNRS) score (Sipe et al., 1984, Neurology, 34,1368-1372). Methods of early and accurate diagnosis of multiplesclerosis and of following the disease progression are described inMattson, 2002, Expert Rev. Neurotherapeutics, 319-328.

Degree of disability of MS patients can be for example measured byKurtzke Expanded Disability Status Scale (EDSS) score (Kurtzke, 1983,Neurology, 33, 1444-1452). Typically a decrease in EDSS scorecorresponds to an improvement in the disease and conversely, an increasein EDSS score corresponds to a worsening of the disease.

Cladribine (2-CdA)

2-CdA and its pharmacologically acceptable salts may be used in thepractice of this invention.

Cladribine can be formulated in any pharmaceutical preparation suitablefor oral administration. Representative oral formulations of 2-CdA aredescribed in (WO 96/19230; WO 96/19229; U.S. Pat. Nos. 6,194,395;5,506,214; WO 2004/087100; WO 2004/087101), the contents of which areincorporated herein by reference. Examples of ingredients for oralformulations are given below.

Processes for preparing 2-CdA are well known in the art. For example,the preparation of 2-CdA is described in (EP 173,059; WO 04/028462; WO04/028462; U.S. Pat. No. 5,208,327; WO 00/64918) and Robins et al., J.Am. Chem. Soc., 1984, 106: 6379. Alternatively, pharmaceuticalpreparations of 2-CdA may be purchased from Bedford Laboratories,Bedford, Ohio.

Oral administration of Cladribine may be in capsule, tablet, oralsuspension, or syrup form. The tablet or capsules may contain from about3 to 500 mg of Cladribine. Preferably they may contain about 3 to about10 mg of Cladribine, more preferably about 3, about 5 or about 10 mg ofCladribine. The capsules may be gelatin capsules and may contain, inaddition to Cladribine in the quantity indicated above, a smallquantity, for example less than 5% by weight, magnesium stearate orother excipient. Tablets may contain the foregoing amount of thecompound and a binder, which may be a gelatin solution, a starch pastein water, polyvinyl alcohol in water, etc. with a typical sugar coating.

Compositions

Compositions of this invention may further comprise one or morepharmaceutically acceptable additional ingredient(s) such as alum,stabilizers, antimicrobial agents, buffers, coloring agents, flavoringagents, adjuvants, and the like.

Compositions of this invention may be in the form of tablets or lozengesformulated in a conventional manner. For example, tablets and capsulesfor oral administration may contain conventional excipients including,but not limited to, binding agents, fillers, lubricants, disintegrantsand wetting agents. Binding agents include, but are not limited to,syrup, accacia, gelatin, sorbitol, tragacanth, mucilage of starch andpolyvinylpyrrolidone. Fillers include, but are not limited to, lactose,sugar, microcrystalline cellulose, maizestarch, calcium phosphate, andsorbitol. Lubricants include, but are not limited to, magnesiumstearate, stearic acid, talc, polyethylene glycol, and silica.Disintegrants include, but are not limited to, potato starch and sodiumstarch glycollate. Wetting agents include, but are not limited to,sodium lauryl sulfate). Tablets may be coated according to methods wellknown in the art.

Compositions of this invention may also be liquid formulationsincluding, but not limited to, aqueous or oily suspensions, solutions,emulsions, syrups, and elixirs. The compositions may also be formulatedas a dry product for constitution with water or other suitable vehiclebefore use. Such liquid preparations may contain additives including,but not limited to, suspending agents, emulsifying agents, nonaqueousvehicles and preservatives. Suspending agent include, but are notlimited to, sorbitol syrup, methyl cellulose, glucose/sugar syrup,gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminumstearate gel, and hydrogenated edible fats. Emulsifying agents include,but are not limited to, lecithin, sorbitan monooleate, and acacia.Nonaqueous vehicles include, but are not limited to, edible oils, almondoil, fractionated coconut oil, oily esters, propylene glycol, and ethylalcohol. Preservatives include, but are not limited to, methyl or propylp-hydroxybenzoate and sorbic acid.

Combination

According to the invention, Cladribine can be administered alone or incombination with IFN-beta, prophylactically or therapeutically to anindividual prior to, simultaneously or sequentially with othertherapeutic regimens or agents (e.g. multiple drug regimens), in atherapeutically effective amount, especially therapeutic agents for thetreatment of multiple sclerosis. Active agents that are administeredsimultaneously with other therapeutic agents can be administered in thesame or different compositions and in the same or different routes ofadministration.

In one embodiment, when Cladribine is administered in combination withWFN-beta, WFN-beta is administered during the Cladribine-free period.

In another embodiment, when Cladribine is administered in combinationwith IFN-beta, IFN-beta is administered after the “treatment” accordingto the invention.

The term “interferon-beta (IFN-β)”, as used herein, is intended toinclude fibroblast interferon in particular of human origin, as obtainedby isolation from biological fluids or as obtained by DNA recombinanttechniques from prokaryotic or eukaryotic host cells, as well as itssalts, functional derivatives, variants, analogs and active fragments.

IFN-β suitable in accordance with the present invention is commerciallyavailable e.g. as Rebif® (Serono), Avonex® (Biogen) or Betaferon®(Schering). The use of interferons of human origin is also preferred inaccordance with the present invention. The term interferon, as usedherein, is intended to encompass salts, functional derivatives,variants, analogs and active fragments thereof.

Rebif® (recombinant human interferon-β) is the latest development ininterferon therapy for multiple sclerosis (MS) and represents asignificant advance in treatment. Rebi® is interferon (IFN)-beta 1a,produced from mammalian cell lines. It was established that interferonbeta-1a given subcutaneously three times per week is efficacious in thetreatment of Relapsing-Remitting Multiple Sclerosis (RRMS). Interferonbeta-1a can have a positive effect on the long-term course of MS byreducing number and severity of relapses and reducing the burden of thedisease and disease activity as measured by MRI.

The dosing of IFN-β in the treatment of relapsing-remitting MS accordingto the invention depends on the type of IFN-β used.

In accordance with the present invention, where IFN is recombinantIFN-β1b produced in E. Coli, commercially available under the trademarkBetaseron®, it may preferably be administered sub-cutaneously everysecond day at a dosage of about of 250 to 300 μg or 8 MIU to 9.6 MIU perperson.

In accordance with the present invention, where IFN is recombinantIFN-β1a, produced in Chinese Hamster Ovary cells (CHO cells),commercially available under the trademark Avonex®, it may preferably beadministered intramuscularly once a week at a dosage of about of 30 μgto 33 μg or 6 MIU to 6.6 MIU per person.

In accordance with the present invention, when IFN is recombinantIFN-β1a, produced in Chinese Hamster Ovary cells (CHO cells),commercially available under the trademark Rebif®, it may preferably beadministered sub-cutaneously three times a week (TIW) at a dosage of 22to 44 μg or 6 MIU to 12 MIU per person.

Patients

Patients according to the invention are patients suffering from multiplesclerosis, preferably RRMS or early SPMS.

In an embodiment of the invention, patients are selected from humanmales or females between 18 and 55 years age.

In another embodiment of the invention, patients had at least onerelapse within the prior 12 months of the treatment.

Use According to the Invention

In one embodiment, the invention provides a use of Cladribine for thepreparation of a pharmaceutical formulation for the treatment ofmultiple sclerosis wherein the formulation is to be orally administeredfollowing the sequential steps below:

-   -   (i) An induction period wherein Cladribine pharmaceutical        formulation is administered and wherein the total dose of        Cladribine reached at the end of the induction period is from        about 1.7 mg/kg to about 3.5 mg/kg;    -   (ii) A Cladribine-free period wherein no Cladribine is        administered;    -   (iii) A maintenance period wherein Cladribine pharmaceutical        formulation is administered and wherein the total dose of        Cladribine reached at the end of the maintenance period is lower        than the total dose of Cladribine reached at the end of the        induction period (i);    -   (iv) A Cladribine-free period wherein no Cladribine is        administered.

In a further embodiment, the invention provides a use according to theinvention wherein the induction period lasts up to about 4 months or upto about 3 months or up to about 2 months.

In a further embodiment, the invention provides a use according to theinvention wherein the induction period lasts up to about 2 months.

In a further embodiment, the invention provides a use according to theinvention wherein the induction period lasts up to about 4 months.

In a further embodiment, the invention provides a use according to theinvention wherein the total dose of Cladribine reached at the end of theinduction period is about 1.7 mg/kg.

In a further embodiment, the invention provides a use according to theinvention wherein the total dose of Cladribine reached at the end of theinduction period is about 3.5 mg/kg.

In another further embodiment, the invention provides a use according tothe invention wherein the Cladribine-free period lasts up to about 10months, or up to about 9 months or up to about 8 months.

In another further embodiment, the invention provides a use according tothe invention wherein the Cladribine-free (ii) period lasts up to about8 months.

In another further embodiment, the invention provides a use according tothe invention wherein the Cladribine-free (ii) period lasts at leastabout 8 months.

In another further embodiment, the invention provides a use according tothe invention wherein the Cladribine-free period (ii) lasts up to about10 months.

In another further embodiment, the invention provides a use according tothe invention wherein the Cladribine-free (iv) period lasts up to about10 months.

In another further embodiment, the invention provides a use according tothe invention wherein the Cladribine-free (iv) period lasts at leastabout 8 months.

In another further embodiment, the invention provides a use according tothe invention wherein the Cladribine-free periods (ii) and/or (iv) lastbetween about 8 and about 10 months.

In another further embodiment, the invention provides a use according tothe invention wherein a placebo-pill is administered during theCladribine-free period.

In another further embodiment, the invention provides a use according tothe invention wherein the Cladribine-free period is free of anyadministration.

In another further embodiment, the invention provides a use according tothe invention wherein the maintenance period lasts up to about 4 months,or up to about 3 months, or up to about 2 months, preferably up to about2 months.

In another further embodiment, the invention provides a use according tothe invention wherein the total dose of Cladribine reached at the end ofthe maintenance period (iii) is about 1.7 mg/kg.

In another further embodiment, the invention provides a use according tothe invention wherein the steps (iii) to (iv) are repeated at least oneor two times.

In a preferred embodiment, the invention provides a use of Cladribinefor the preparation of a pharmaceutical formulation for the treatment ofmultiple sclerosis wherein the formulation is to be orally administeredfollowing the sequential steps below:

-   -   (i) An induction period wherein Cladribine pharmaceutical        formulation is administered and wherein the total dose of        Cladribine reached at the end of the induction period is from        about 1.7 mg/kg to about 3.5 mg/kg;    -   (ii) A Cladribine-free period wherein no Cladribine is        administered;    -   (iii) A maintenance period wherein Cladribine pharmaceutical        formulation is administered and wherein the total dose of        Cladribine reached at the end of the maintenance period is lower        than the total dose of Cladribine reached at the end of the        induction period (i)    -   (iv) A Cladribine-free period wherein no Cladribine is        administered;        wherein the induction period last up to about 4 months, or up to        about 3 months, or up to about 2 months; the Cladribine-free        period (ii) lasts up to about 10 months, or up to about 9        months, or up to about 8 months; the maintenance period (iii)        lasts up to about 2 months; the Cladribine-free period (iv)        lasts up to about 10 months; the total dose of Cladribine        reached at the end of the maintenance period is about 1.7 mg/kg        and steps (iii) to (iv) are repeated performed one, two or three        times.

In another embodiment, the invention provides a use of Cladribine forthe preparation of a pharmaceutical formulation for the treatment ofmultiple sclerosis wherein the formulation is to be orally administeredfollowing the sequential steps below:

-   -   (i) An induction period wherein Cladribine pharmaceutical        formulation is administered and wherein the total effective dose        of Cladribine reached at the end of the induction period is from        about 0.7 mg/kg to about 1.4 mg/kg;    -   (ii) A Cladribine-free period wherein no Cladribine is        administered;    -   (iii) A maintenance period wherein Cladribine pharmaceutical        formulation is administered and wherein the total effective dose        of Cladribine reached at the end of the maintenance period (iii)        is lower than the total effective dose of Cladribine reached at        the end of the induction period (i);    -   (iv) A Cladribine-free period wherein no Cladribine is        administered.

In a further embodiment, the invention provides a use of Cladribine forthe preparation of a pharmaceutical formulation for the treatment ofmultiple sclerosis wherein the formulation is to be orally administeredfollowing the sequential steps below:

-   -   (i) An induction period wherein Cladribine pharmaceutical        formulation is administered and wherein the total effective dose        of Cladribine reached at the end of the induction period is from        about 0.7 mg/kg to about 1.4 mg/kg;    -   (ii) A Cladribine-free period wherein no Cladribine is        administered;    -   (iii) A maintenance period wherein Cladribine pharmaceutical        formulation is administered and wherein the total effective dose        of Cladribine reached at the end of the maintenance period is        lower than the total effective dose of Cladribine reached at the        end of the induction period (i);    -   (iv) A Cladribine-free period wherein no Cladribine is        administered;        wherein the induction period lasts up to about 4 months, or up        to about 3 months, or up to about 2 months; the Cladribine-free        period (ii) lasts up to about 10 months, or up to about 9        months, or up to about 8 months; the maintenance period (iii)        lasts up to about 2 months; the Cladribine-free period (ii)        lasts up to about 10 months; the total effective dose of        Cladribine reached at the end of the maintenance period is about        0.7 mg/kg and steps (iii) to (iv) are repeated performed one,        two or three times.

In a preferred embodiment, the invention provides Cladribine for use asa medicament for the treatment of multiple sclerosis wherein themedicament is to be orally administered following the sequential stepsbelow:

-   -   (i) An induction period wherein Cladribine pharmaceutical        formulation is administered and wherein the total dose of        Cladribine reached at the end of the induction period is from        about 1.7 mg/kg to about 3.5 mg/kg;    -   (ii) A Cladribine-free period wherein no Cladribine is        administered;    -   (iii) A maintenance period wherein Cladribine pharmaceutical        formulation is administered and wherein the total dose of        Cladribine reached at the end of the maintenance period is lower        than the total dose of Cladribine reached at the end of the        induction period (i);    -   (iv) A Cladribine-free period wherein no Cladribine is        administered;        wherein the induction period last up to about 4 months, or up to        about 3 months, or up to about 2 months; the Cladribine-free        period (ii) lasts up to about 10 months, or up to about 9        months, or up to about 8 months; the maintenance period (iii)        lasts up to about 2 months; the Cladribine-free period (iv)        lasts up to about 10 months; the total dose of Cladribine        reached at the end of the maintenance period is about 1.7 mg/kg        and steps (iii) to (iv) are repeated performed one, two or three        times.

In another embodiment, the invention provides a use of Cladribineaccording to the invention wherein the pharmaceutical formulation is tobe orally administered at a daily dose of Cladribine about 3 to 30 mgCladribine, preferably 5 to 20 mg Cladribine, most preferably 10 mgCladribine.

In another further embodiment, the invention provides a use according tothe invention wherein the total dose of Cladribine reached at the end ofthe induction period is about 3.5 mg/kg and the total dose of Cladribinereached at the end of the maintenance period is about 1.7 mg/kg.

In another further embodiment, the invention provides a use according tothe invention wherein the total effective dose of Cladribine reached atthe end of the induction period is about 1.4 mg/kg and the totaleffective dose of Cladribine reached at the end of the maintenanceperiod is about 0.7 mg/kg.

In another embodiment, the invention provides a use of Cladribineaccording to the invention wherein the pharmaceutical formulation is tobe orally administered once a day during the induction period.

In another embodiment, the invention provides a use of Cladribineaccording to the invention wherein the pharmaceutical formulation is tobe orally administered several times a day administered once a dayduring the induction period, preferably twice or three times a day, morepreferably twice a day.

In another embodiment, the invention provides a use of Cladribineaccording to the invention whereby the pharmaceutical formulation isorally administered about 1 to about 7 days per month, preferably fromabout 5 to about 7 days per month during the induction period.

In another embodiment, the invention provides a use of Cladribineaccording to the invention whereby the pharmaceutical formulation isorally administered about 0.02 days/kg to about 0.08 days/kg per monthduring the induction period.

In another embodiment, the invention provides a use of Cladribineaccording to the invention whereby the pharmaceutical formulation isorally administered about 0.02 days/kg to about 0.08 days/kg per monthduring the maintenance period.

In another embodiment, the invention provides a use of Cladribineaccording to the invention wherein the pharmaceutical formulation is tobe orally administered at a daily dose of about 10 mg Cladribine fromday 1 to about day 2 each month during the induction period.

In another embodiment, the invention provides a use of Cladribineaccording to the invention wherein the pharmaceutical formulation is tobe orally administered at a daily dose of about 10 mg Cladribine fromday 1 to about day 3 each month during the induction period.

In another embodiment, the invention provides a use of Cladribineaccording to the invention wherein the pharmaceutical formulation is tobe orally administered at a daily dose of about 10 mg Cladribine fromday 1 to about day 4 each month during the induction period.

In another embodiment, the invention provides a use of Cladribineaccording to the invention wherein the pharmaceutical formulation is tobe orally administered at a daily dose of about 10 mg Cladribine fromday 1 to about day 5 each month during the induction period.

In another embodiment, the invention provides a use of Cladribineaccording to the invention wherein the pharmaceutical formulation is tobe orally administered at a daily dose of about 10 mg Cladribine fromday 1 to about day 6 each month during the induction period.

In another embodiment, the invention provides a use of Cladribineaccording to the invention wherein the pharmaceutical formulation is tobe orally administered at a daily dose of about 10 mg Cladribine fromday 1 to about day 4 each month during the induction period and whereinthe pharmaceutical formulation is a pharmaceutical formulation describedin WO 2004/087101 or in WO 2004/087100.

In another embodiment, the invention provides a use of Cladribineaccording to any of the preceding claims wherein the pharmaceuticalformulation is to be administered in combination with interferon-beta.

In a preferred embodiment, the invention provides a method for thetreatment of multiple sclerosis, comprising the oral administration ofCladribine or of a pharmaceutical formulation thereof in a patient inneed thereof comprising the following steps:

-   -   (i) An induction period wherein Cladribine or a pharmaceutical        formulation thereof is administered and wherein the total dose        of Cladribine reached at the end of the induction period is from        about 1.5 mg/kg to about 3.5 mg/kg;    -   (ii) A Cladribine-free period wherein no Cladribine is        administered;    -   (iii) A maintenance period wherein Cladribine or a        pharmaceutical formulation thereof is administered and wherein        the total dose of Cladribine reached at the end of the        maintenance period is lower than the total dose of Cladribine        reached at the end of the induction period (i);    -   (iv) A Cladribine-free period wherein no Cladribine is        administered.

In a preferred embodiment, the invention provides a method for thetreatment of multiple sclerosis, comprising the oral administration ofCladribine or of a pharmaceutical formulation thereof in a patient inneed thereof comprising the following steps:

-   -   (i) An induction period wherein Cladribine or a pharmaceutical        formulation thereof is administered and wherein the total        effective dose of Cladribine reached at the end of the induction        period is from about 0.7 mg/kg to about 1.4 mg/kg;    -   (ii) A Cladribine-free period wherein no Cladribine is        administered;    -   (iii) A maintenance period wherein Cladribine pharmaceutical        formulation is administered and wherein the total effective dose        of Cladribine reached at the end of the maintenance period is        lower than the total effective dose of Cladribine reached at the        end of the induction period (i);    -   (iv) A Cladribine-free period wherein no Cladribine is        administered.

In another further embodiment, the invention provides a method accordingto the invention wherein the steps (iii) to (iv) are repeated at leastone or two times.

In a preferred embodiment, the invention provides a method of treatingmultiple sclerosis with Cladribine, wherein Cladribine is orallyadministered following the sequential steps below:

-   -   (i) Administering Cladribine, such that the total dose of        Cladribine reached at the end of the induction period is from        about 1.7 mg/kg to about 3.5 mg/kg;    -   (ii) Administering no Cladribine during a Cladribine free        period;    -   (iii) Administering Cladribine such that the total dose of        Cladribine reached at the end of a maintenance period is lower        than the total dose of Cladribine reached at the end of the        induction period (i);    -   (iv) And optionally, a Cladribine-free period wherein no        Cladribine is administered.

In a further preferred embodiment, the invention provides a methodwherein the induction period lasts up to about 4 months, or up to about3 months, or up to about 2 months.

In a further preferred embodiment, the invention provides a methodwherein the total dose of Cladribine reached at the end of the inductionperiod is about 1.7 mg/kg.

In a further preferred embodiment, the invention provides a methodwherein the total dose of Cladribine reached at the end of the inductionperiod is about 3.5 mg/kg.

In a further preferred embodiment, the invention provides a methodwherein the total effective dose of Cladribine reached at the end of theinduction period is about 1.4 mg/kg.

In a further preferred embodiment, the invention provides a methodwherein the Cladribine-free period lasts up to about 10 months, or up toabout 9 months, or up to about 8 months.

In a further preferred embodiment, the invention provides a methodwherein the maintenance period lasts up to about 4 months, or up toabout 3 months or up to about 2 months.

In a further preferred embodiment, the invention provides a methodwherein the total dose of Cladribine reached at the end of themaintenance period is about 1.7 mg/kg.

In a further preferred embodiment, the invention provides a methodwherein the total effective dose of Cladribine reached at the end of themaintenance period is about 0.7 mg/kg.

In a further preferred embodiment, the invention provides a methodwherein the maintenance period is followed by a Cladribine-free period.

In another further embodiment, the invention provides a method accordingto the invention wherein the total dose of Cladribine reached at the endof the induction period is about 3.5 mg/kg and the total dose ofCladribine reached at the end of the maintenance period is about 1.7mg/kg.

In another further embodiment, the invention provides a method accordingto the invention wherein the total effective dose of Cladribine reachedat the end of the induction period is about 1.4 mg/kg and the totaleffective dose of Cladribine reached at the end of the maintenanceperiod is about 0.7 mg/kg.

In another further embodiment, the invention provides a method accordingto the invention wherein Cladribine is to be orally administered at adaily dose of about 3 to about 30 mg.

In another further embodiment, the invention provides a method accordingto the invention wherein Cladribine is to be orally administered at adaily dose of about 10 mg.

In another further embodiment, the invention provides a method accordingto the invention wherein Cladribine is orally administered about 1 toabout 7 days per month during the induction period.

In another further embodiment, the invention provides a method accordingto the invention wherein the steps (iii) are repeated at least one ortwo times.

In another further embodiment, the invention provides a method accordingto the invention wherein Cladribine is to be administered in combinationwith interferon-beta.

EXAMPLES

The following abbreviations refer respectively to the definitions below:

kg (kilogram), μg (microgram), mg (milligram), AEs (Adverse effects),CNS (Cnetral nervous system), CSF (Cerebrospinal fluid), EDSS (ExpandedDisability Status Scale, SNRS (Scripps Neurologic Rating Scale), IFN(interferon), i.v. (intra-veinous), MIU (Million International units),MS (multiple sclerosis), MRI (Magnetic resonance imaging), p.o. (peros), PPMS (Primary progressive multiple sclerosis), PRMS (Progressiverelapsing multiple sclerosis), RRMS (Relapsing-remitting multiplesclerosis), SPMS (Secondary progressive multiple sclerosis), s.c.(subcutaneous), TIW (Three times a week), 2-CdA(2-chloro-2′deoxyadenosine or Cladribine), UI; (International unit).

The efficacy and safety of oral Cladribine administration, eventuallymulti-dose administration, according to the invention can be assessedfor example following the protocol below:

Example 1 Oral Cladribine in the Treatment of Relapsing Forms of MS

A study of sixty patients with relapsing forms of clinically definitemultiple sclerosis is undertaken. Each patient is first examined fornormal hepatic, renal, and bone marrow functioning to establish baselinevalues.

Patients are selected from Male or Female, between 18 and 55 years ofage who had one or more relapses within the prior 12 months. Femalepatients are non-pregnant female. Patients are randomly assigned to oneof the treatment groups listed in Table 1 below:

TABLE 1 Group 2-CdA 1 — 2 1.75 mg/kg 3  3.5 mg/kg

Each of the patients in Groups 2 and 3 receives 3 mg or 10 mg 2-CdA (1,2 or 3 administration(s) a day depending on the patient's weight)combined in cyclodextrin formulation as described in WO 2004/087101,Example 3. The Compositions of the Cladribine formulations in 3 mg or 10mg 2-CdA tablets containing hydroxypropyl-beta-cyclodextrin are listedin Table 2 below:

TABLE 2 Formula Formula Name of ingredients mg/tablet mg/tabletCladribine-2- 153.75 30.60 hydroxypropyl-β- equivalent to equivalent tocyclodextrin- complex* 10 mg 2-CdA 3 mg 2-CdA Sorbitol powder 44.25 68.4Magnesium Stearate 2.0 1.00 (vegetable grade) Total 200.0 100*Cladribine is complexed and lyophilised with2-hydroxypropyl-β-cyclodextrin as a separate process as described in WO2004/087101.

Examples of administration schemes for the induction period depending onthe patient's weight are given below in Tables 3 and 4 for the targetdoses of 1.75 mg/kg and 3.5 mg/kg respectively. For the maintenanceperiod, the example of administration scheme of Table 3 is applicable.

TABLE 3 Patient weight Total target dose Number of pills ranges (kg)(kg) equivalent (10 mg)/induction period Mid to 1.75 mg/kg Month MonthMin range Max Min Max 1 2 Total 40 42.5 44.9 28 31.4 4 3 7 45 47.5 49.931.5 34.9 4 4 8 50 52.5 54.9 35 38.4 5 4 9 55 57.5 59.9 38.5 41.9 5 5 1060 62.5 64.9 42 45.4 5 5 10 65 67.5 69.9 45.5 48.9 6 5 11 70 72.5 74.949 52.4 6 6 12 75 77.5 79.9 52.5 55.9 7 6 13 80 82.5 84.9 56 59.4 7 6 1385 87.5 89.9 59.5 62.9 7 7 14 90 92.5 94.9 63 66.4 8 7 15 95 97.5 99.966.5 69.9 8 8 16 100 102.5 104.9 70 73.4 9 8 17 105 107.5 109.9 73.576.9 9 9 18 110 112.5 114.9 77 80.4 9 9 18 115 117.5 119.9 80.5 83.9 109 19

TABLE 4 Patient weight Total target dose Number of pills ranges (kg)(kg) equivalent (10 mg)/induction period Mid to 3.5 mg/kg Month MonthMonth Month Min range Max Min Max 1 2 3 4 Total 40 42.5 44.9 56 62.9 4 43 3 14 45 47.5 49.9 63 69.9 4 4 4 4 16 50 52.5 54.9 70 76.9 5 4 4 4 1755 57.5 59.9 77 83.9 5 5 5 4 19 60 62.5 64.9 84 90.9 6 5 5 5 21 65 67.569.9 91 97.9 6 6 5 5 22 70 72.5 74.9 98 104.9 6 6 6 6 24 75 77.5 79.9105 111.9 7 7 6 6 26 80 82.5 84.9 112 118.9 7 7 7 6 27 85 87.5 89.9 119125.9 7 7 7 7 28 90 92.5 94.9 126 132.9 8 8 7 7 30 95 97.5 99.9 133139.9 8 8 8 8 32 100 102.5 104.9 140 146.9 9 8 8 8 33 105 107.5 109.9147 153.9 9 9 9 8 35 110 112.5 114.9 154 160.9 10 9 9 9 37 115 117.5119.9 161 167.9 10 10 9 9 38

In Group 1 patients receive a placebo (saline) for 4 months followed by8 months of no treatment.

In Group 2 patients receive a daily oral administration of Cladribinefor about 5 days a month during 2 months (induction period) of 2-CdAcyclodextrin formulation such as the total effective dose administeredat the end of the first 2 months approximates about 0.7 mg/kg (totaldose of about 1.75 mg/kg for a bioavailability of about 40%); followedby administration of placebo for 2 months; followed by 8 months of notreatment.

In Group 3 patients receive a daily oral administration of Cladribinefor about 5 days a month during 4 months (induction period) of 2-CdAcyclodextrin formulation such as the total effective dose administeredat the end of the first 4 months approximates about 1.4 mg/kg (totaldose of about 3.5 mg/kg for a bioavailability of about 40%); followed by8 months of no treatment.

Beginning at month 13, all 3 patient groups receive re-treatment withCladribine cyclodextrin formulation for about 5 days a month for 2months (maintenance period) with the lower dose (such as the totaleffective dose administered at the end of the first 2 monthsapproximates about 0.7 mg/kg) followed by 10 months of no treatment.

Finally, beginning at month 25, all patient groups receive re-treatmentwith Cladribine cyclodextrin formulation for about 5 days a month for 2months (maintenance period) with the lower dose (such as the totaleffective dose administered at the end of the first 2 monthsapproximates about 0.7 mg/kg) followed by 10 more months of notreatment.

Patients are monitored to determine whether there is any progression orimprovement of brain lesions associated with progression of MS throughMRI scans and neurological examination as described in Miller et al.,1996, above; Evans et al., 1997, above; Sipe et al., 1984, above; andMattson, 2002, above. All patients have a baseline and MRI study (brainor spinal cord, according to localization of the lesions) at month 12.

The patient's disability progression and the time for having a firstrelapse are monitored as well as the proportion of relapse-fee patientsat 24 months.

Lymphocyte markers and monocyte counts are monitored in the patients.

Patients in Groups 2 and 3 have a decrease in brain lesions.

The data show that the 2-CdA regimen consisting in the succession of aninduction treatment and maintenance treatments is efficient indecreasing brain lesions and no severe adverse effect is observed.

1. A method of treating multiple sclerosis comprising the oraladministration of a formulation comprising cladribine, wherein theformulation is to be orally administered following the sequential stepsbelow: (i) an induction period wherein said cladribine formulation isadministered and wherein the total dose of cladribine reached at the endof the induction period is from about 1.7 mg/kg to about 3.5 mg/kg; (ii)a cladribine-free period of between about 8 and about 10 months whereinno cladribine formulation is administered; (iii) a maintenance periodwherein said cladribine formulation is administered and wherein thetotal dose of cladribine reached at the end of the maintenance period islower than the total dose of cladribine reached at the end of theinduction period (i); and (iv) a cladribine-free period wherein nocladribine formulation is administered.
 2. The method according to claim1, wherein the induction period lasts up to about 4 months.
 3. Themethod according to claim 2, wherein the induction period lasts about 2months.
 4. The method according to claim 2, wherein the induction periodlasts about 3 months.
 5. The method according to claim 2, wherein theinduction period lasts about 4 months.
 6. The method according to claim2, wherein the induction period lasts up to about 3 months.
 7. Themethod according to claim 1, wherein the total dose of cladribinereached at the end of the induction period is about 1.7 mg/kg.
 8. Themethod according to claim 1, wherein the total dose of cladribinereached at the end of the induction period is about 3.5 mg/kg.
 9. Themethod according to claim 1, wherein the cladribine-free (iv) periodlasts about 10 months.
 10. The method according to claim 1, wherein themaintenance period lasts about 4 months.
 11. The method according toclaim 1, wherein the total dose of cladribine reached at the end of themaintenance period is about 1.7 mg/kg.
 12. The method according to claim1, wherein the formulation is to be orally administered following thesequential steps below: (i) an induction period wherein said cladribineformulation is orally administered and wherein the total dose ofcladribine reached at the end of the induction period is from about 1.7mg/kg to about 3.5 mg/kg; (ii) a cladribine-free period of between about8 and about 10 months wherein no cladribine formulation is administered;(iii) a maintenance period wherein said cladribine formulation isadministered and wherein the total dose of cladribine reached at the endof the maintenance period is lower than the total dose of cladribinereached at the end of the induction period (i); and (iv) acladribine-free period wherein no cladribine formulation isadministered; wherein the induction period lasts up to 4 months; thecladribine-free period (ii) lasts up to 10 months; the maintenanceperiod (iii) lasts up to 2 months; the cladribine-free period (iv) lastsup to 10 months; the total dose of cladribine reached at the end of themaintenance period is about 1.7 mg/kg and steps (iii) to (iv) arerepeated one, two or three times.
 13. The method according to claim 12,wherein the total dose of cladribine reached at the end of the inductionperiod is about 3.5 mg/kg and the total dose of cladribine reached atthe end of the maintenance period is about 1.7 mg/kg.
 14. The methodaccording to claim 12, wherein the formulation is to be orallyadministered at a daily dose of 3 to 30 mg cladribine.
 15. The methodaccording to claim 14, wherein the formulation is to be orallyadministered at a daily dose of 10 mg cladribine.
 16. The methodaccording to claim 1, wherein the formulation is orally administered 1to 7 days per month during the induction period.
 17. The methodaccording to claim 1, wherein the steps (iii) to (iv) are repeated atleast one or two times.
 18. The method according to claim 1, whereinsaid cladribine formulation is to be administered in combination withinterferon-beta.
 19. The method according to claim 12, wherein saidcladribine formulation is to be administered in combination withinterferon-beta.
 20. A method of treating multiple sclerosis comprisingthe oral administration of a formulation comprising cladribine followingthe sequential steps below: (i) an induction period lasting from about 2months to about 4 months wherein said formulation is orally administeredand wherein the total dose of cladribine reached at the end of theinduction period is from about 1.7 mg/kg to about 3.5 mg/kg; (ii) acladribine-free period lasting from about 8 months to about 10 months,wherein no cladribine is administered; (iii) a maintenance periodlasting from about 2 months to about 4 months, wherein said formulationis orally administered and wherein the total dose of cladribine reachedat the end of the maintenance period is lower than the total dose ofcladribine reached at the end of the induction period (i); (iv) acladribine-free period wherein no cladribine is administered.
 21. Themethod according to claim 20, wherein the induction period lasts about 4months.
 22. The method according to claim 20, wherein the inductionperiod lasts about 2 months.
 23. The method according to claim 20,wherein the total dose of cladribine reached at the end of the inductionperiod is about 1.7 mg/kg.
 24. The method according to claim 20, wherethe total dose of cladribine reached at the end of the induction periodis about 3.5 mg/kg.
 25. The method according to claim 20, wherein thecladribine-free period (ii) lasts about 10 months.
 26. The methodaccording to claim 20, wherein the cladribine-free (iv) period lasts 10months.
 27. The method according to claim 20, wherein the maintenanceperiod lasts about 2 months.
 28. The method according to claim 20,wherein the formulation is orally administered following the sequentialsteps below: (i) an induction period wherein said formulation isadministered orally and wherein the total dose of cladribine reached atthe end of the induction period is from about 1.7 mg/kg to about 3.5mg/kg; (ii) a cladribine-free period wherein no cladribine isadministered; (iii) a maintenance period wherein said formulation isadministered orally and wherein the total dose of cladribine reached atthe end of the maintenance period is lower than the total dose ofcladribine reached at the end of the induction period (i); (iv) acladribine-free period wherein no cladribine is administered; whereinthe maintenance period (iii) lasts about 2 months; the cladribine-freeperiod (iv) lasts about 10 months; the total dose of cladribine reachedat the end of the maintenance period is about 1.7 mg/kg and steps (iii)to (iv) are repeatedly performed one, two or three times.
 29. The methodaccording to claim 20, wherein the total dose of cladribine reached atthe end of the induction period is about 3.5 mg/kg and the total dose ofcladribine reached at the end of the maintenance period is about 1.7mg/kg.
 30. The method according to claim 20, wherein the formulation isorally administered at a daily dose of 3 to 30 mg cladribine.
 31. Themethod according to claim 20, wherein the formulation is orallyadministered at a daily dose of 10 mg cladribine.
 32. The methodaccording to claim 20, wherein the formulation is orally administered 1to 7 days per month during the induction period.
 33. The methodaccording to claim 20, wherein the steps (iii) to (iv) are repeated atleast one time.
 34. The method according to claim 20, wherein the steps(iii) to (iv) are repeated at least two times.
 35. The method accordingto claim 20, wherein the formulation is administered in combination withinterferon-beta.
 36. A method of treating multiple sclerosis comprisingthe oral administration of a formulation comprising cladribine followingthe sequential steps below: (i) an induction period lasting from about 2months to about 4 months wherein said formulation is orally administeredand wherein the total dose of cladribine reached at the end of theinduction period is from about 1.7 mg/kg to about 3.5 mg/kg; (ii) acladribine-free period lasting from about 8 months to about 10 months,wherein no cladribine is administered; (iii) a maintenance periodlasting from about 2 months to about 4 months, wherein said formulationis orally administered and wherein the total dose of cladribine reachedat the end of the maintenance period is about 1.7 mg/kg; (iv) acladribine-free period wherein no cladribine is administered.
 37. Themethod according to claim 36, wherein the induction period lasts about 4months.
 38. The method according to claim 36, wherein the inductionperiod lasts about 2 months.
 39. The method according to claim 36,wherein the total dose of cladribine reached at the end of the inductionperiod is about 1.7 mg/kg.
 40. The method according to claim 36, wherethe total dose of cladribine reached at the end of the induction periodis about 3.5 mg/kg.
 41. The method according to claim 36, wherein thecladribine-free period (ii) lasts about 10 months.
 42. The methodaccording to claim 36, wherein the cladribine-free (iv) period lasts 10months.
 43. The method according to claim 36, wherein the maintenanceperiod lasts about 2 months.
 44. The method according to claim 36,wherein the formulation is orally administered at a daily dose of 3 to30 mg cladribine.
 45. The method according to claim 36, wherein theformulation is orally administered at a daily dose of 10 mg cladribine.46. The method according to claim 36, wherein the formulation is orallyadministered 1 to 7 days per month during the induction period.
 47. Themethod according to claim 36, wherein the steps (iii) to (iv) arerepeated at least one or two times.
 48. The method according to claim36, wherein the formulation is administered in combination withinterferon-beta.